• 2019-10
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  • br Loss of E cadherin contributes


    3.6. Loss of E-cadherin contributes to activin A-stimulated ovarian cancer cell migration
    Transwell migration assay was used to evaluate whether loss of E-cadherin contributes to enhanced ovarian cancer cell migration induced by activin A. Treatment with activin A significantly increased cell mi-gration ability in both SKOV3 and OVISE Methoxy-X04 (Fig. 8A and B, respec-tively). Next, we exogenously overexpressed full-length human E-
    Y. Yi, et al. Experimental Cell Research xxx (xxxx) xxx–xxx
    Fig. 4. Activin A suppresses E-cadherin via SNAIL and SLUG in ovarian cancer cells.
    cadherin to explore the role of E-cadherin in activin A-induced SKOV3 and OVISE cell migration. Importantly, the pro-migratory effect of ac-tivin A in SKOV3 and OVISE cells was attenuated by forced-expression of E-cadherin. Taken together, these results suggest that down-regulation of E-cadherin mediates activin A-increased cell migration of human ovarian cancer cells.
    4. Discussion
    Most ovarian cancers are diagnosed at advanced stage with wide-spread metastasis, which is a major cause for the high mortality rate of ovarian cancer (Bhoola and Hoskins 2006). The most common route of epithelial ovarian cancer metastasis is through shedding ovarian cancer cells from the primary tumor into the peritoneal fluid, with surviving cancer cells subsequently adhering to peritoneal tissues to form sec-ondary lesions (Lengyel 2010). The classical hematogenous route of metastasis, in which cancer cells disseminate via the bloodstream or lymphatic system, has also been reported in epithelial ovarian cancer 
    (Feki et al., 2009; Pradeep et al., 2014). Increased signaling by activin A has been implicated in the development or progression of many endo-crine-related cancers [7,20]. Both clinical and experimental studies detect activin A and its receptors in human ovarian cancer cell lines and ovarian epithelial tumors [21,22]. Elevated activin A levels have been demonstrated in ovarian epithelial cancer patient serum, cyst fluid, and peritoneal fluid [8]. In ovarian cancer cells, activin A has been shown to stimulate cell proliferation, migration and invasion [23,24]. Consistent with these observations, our results highlight that exogenous activin A increases SKOV3 and OVISE cell migration. Ovarian cancer cells un-dergo an epithelial-to-mesenchymal transition (EMT) before the meta-static process [25]. EMT facilitates epithelial cancer cell detachment from the basement membrane and the loss of intercellular adhesions with neighboring cells via the acquisition of mesenchymal migratory and invasive traits [26]. These changes occur with the alteration in expression of cell-cell and cell-matrix adhesion molecules, including E-cadherin [27]. Downregulation of E-cadherin has been described in ovarian cancer cells floating in ascites and at metastatic sites compared
    Y. Yi, et al. Experimental Cell Research xxx (xxxx) xxx–xxx
    Fig. 5. Activin A induces SMAD2 and SMAD3 but not AKT and ERK1/2 phosphorylation.
    with those in the primary ovarian tumor [28]. In addition, reduced E-cadherin levels have also been associated with poor patient survival [12,29]. Ovarian cancer cells expressing low levels of E-cadherin are more invasive [30]. Indeed, a recent study has shown that treatment with activin A results in mesenchymal cell-like morphologic changes that are associated with increased invasion of OAW-42 human ovarian cancer cells [31]. Our in vitro data show that overexpression of E-cad-herin inhibits basal migration in SKOV3 cells, confirming that E-cad-herin suppresses ovarian cancer cell migration. More importantly, E-cadherin expression is decreased by activin A in SKOV3 and OVISE cells, and E-cadherin overexpression diminishes activin A-induced SKOV3 and OVISE cell invasion. These results emphasize the role of activin A in the development and progression of ovarian cancer.